Progesterone is a unique reproductive hormone, and it plays a decisive role for tissues of female reproduction. Its principal target organs are uterus, ovary, breast and the hypothalamus-pituitary axis. In addition to the primary use as pregnancy control for women (e.g., oral contraception (OC)), progestins, optionally combined with estrogens, are widely used in hormone replacement therapy (HRT). Progestins are also used to treat several gynecological disorders, e.g., dysmenorrhea, endometriosis, and dysfunctional uterine bleeding caused by hormonal deficiency or imbalance. Due to certain effects of progestins, which may be undesirable for some applications, or cross-reactivities with receptors other than the progesterone receptor, the development of new generations of progestins to improve their activity profile has been a great challenge. Additionally, the exploration of therapeutic applications such as oncology demands progestins with new activity profiles.
Recently, non-steroidal progestins with a very strong affinity to the progesterone receptor, but with additional androgen activity were disclosed in WO 98/54159. These progestins are not only suitable for female fertility control (FC) and HRT (optionally in combination with estrogens), but may also be used for male FC, male HRT and for treating andrological syndromes.
WO 00/32584 discloses specific non-steroidal glucocorticoids exhibiting a clear dissociation between anti-inflammatory activity and metabolic effects, while their progestagenic potential is less pronounced although their affinity for the progesterone receptor is high.
Finally, DE 100 38 639.3 discloses glucocorticoids exhibiting a strong affinity for the glucocorticoid receptor and having thus anti-inflammatory as well as additional anti-allergic, immunosuppressive and anti-proliferative activity for treating diseases including arthritis, allergies etc.
However, in particular in the area of female FC and HRT there is a strong need for progestins having low affinity for other hormone receptors, but exhibiting instead a strong dissociation between different PR target tissues or organs, such as in the breast and in the reproductive tract.
In particular, the provision of a dissociated progestin with an antiproliferative potential in the breast tissue and, at the same time, beneficial effects in the endometrium seems desirable, as there is a number of epidemiological studies about the relation between breast cancer incidence and use of combined oral contraceptives (COCs) or HRT, especially with respect to extended periods of use (see e.g., K. E. Malone et al., Epidemiologic Reviews 1993, 15, 80-97 and Standford et al., Epidemiologic Reviews 1993, 15, 98-107). Although the risks are contradictory and controversial, there is evidence that many years of intake under certain circumstances might enhance the mitotic activity of normal breast epithelial cells. Therefore, a dissociated activity profile of progestins regarding the provision of beneficial, e.g. antiproliferative, effects in the breast, but with the classical progestagenic effects in the ovary and/or uterus is desirable.
Recently, assays for screening for progesterone receptor ligands exhibiting tissue-specificity have been provided, cf. PCT/EP01/15200 (U.S. Pat. No. 60/305,875). One approach of screening for progesterone receptor (PR) ligands with a dissociated activity profile was based on the fact that the PR is expressed in two different isoforms (PR-A and PR-B) which seem to be capable of being activated independently of each other by compounds having a selectivity for either PR-A or PR-B.
Both PR-isoforms are expressed in all progesterone target organs tested so far (e.g. breast, uterus). However, there is strong evidence that PR-A and PR-B function in a tissue-specific manner to mediate responses to progesterone. Isoform-specific knock-out mice show different functions of PR-A and PR-B in the same target organ. Based on these studies, PR-B seems to be the most responsible receptor for mammary gland proliferation and differentiation, whereas the antiproliferative action of progestins on the uterine epithelium and on ovulation is most likely mediated by PR-A (B. Mulac-Jericevic, Science 2000, 289, 1751-1754; Orla Conneely, Endocrine Society Meeting, Toronto, June 2000).
Thus, the invention disclosed in PCT/EP1/15200 was based on the new theory that isoform-specific ligands of PR activity may allow tissue-selective modulation of progestin activity in hormonal therapy and contraception. However, while PCT/EP01/15200 (U.S. Ser. No. 60/305,875) provided a tool for identifying potentially PR-isoform and/or tissue-specific PR ligands, the present invention provides specific non-steroidal progestins exhibiting pronounced PR isoform selectivity as well as a surprising dissociated effect on different PR target organs, in particular a uterus/breast dissociated activity profile.